A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cells

Ning, Ke; Miller, Lisa C.; Laidlaw, Hilary A; Burgess, Laura; Perera, Nevin M; Downes, C P; Leslie, Nicholas R.; Ashford, M. L. J.

doi:10.1038/sj.emboj.7601118

Cited by 102 publications

(121 citation statements)

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“…We show that phosphorylation of the C terminus controls an intramolecular interaction that determines the fraction of PTEN associated with the membrane and thereby the set point for cellular PIP 3 . In fact, there is some evidence that phosphorylation of PTEN can be regulated (35). It is likely that the set point is regulated in different tissues by controlling the level of phosphorylation of the cluster.…”

Section: Discussionmentioning

confidence: 99%

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A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN

Rahdar

Inoue²,

Meyer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

245

289

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The PI 3-phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10), one of the most important tumor suppressors, must associate with the plasma membrane to maintain appropriate steady-state levels of phosphatidylinositol 3,4,5-triphosphate. Yet the mechanism of membrane binding has received little attention and the key determinants that regulate localization, a phosphatidylinositol 4,5-bisphosphate (PIP2) binding motif and a cluster of phosphorylated C-terminal residues, were not included in the crystal structure. We report that membrane binding requires PIP2 and show that phosphorylation regulates an intramolecular interaction. A truncated version of the enzyme, PTEN1-351, bound strongly to the membrane, an effect that was reversed by co-expression of the remainder of the molecule, PTEN352-403. The separate fragments associated in vitro, an interaction dependent on phosphorylation of the C-terminal cluster, a portion of the PIP2 binding motif, integrity of the phosphatase domain, and the CBR3 loop. Our investigation provides direct evidence for a model in which PTEN switches between open and closed states and phosphorylation favors the closed conformation, thereby regulating localization and function. Small molecules targeting these interactions could potentially serve as therapeutic agents in antagonizing Ras or PI3K-driven tumors. The study also stresses the importance of determining the structure of the native enzyme.iRAP ͉ phosphatase ͉ PI3K ͉ PIP2 ͉ PIP3 P TEN (phosphatase and tensin homologue deleted on chromosome 10) is a lipid phosphatase that dephosphorylates phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) and opposes PI3K signaling (1). This important tumor suppressor is frequently mutated in endometrium, prostate, and brain cancer, and alterations of PTEN activity leads to Cowden and Bannayan-Zonana syndromes in which patients develop benign hamartomas (2-4). Mice homozygous for a deletion of PTEN die in early embryogenesis whereas heterozygotes have a propensity to develop widespread neoplasms (5). Prostate-directed conditional deletions of PTEN result in metastatic prostate cancer (6-8). Neural and astrocyte-specific deletions lead to greatly enlarged brain size and abnormalities in astrocytes and neurons (9). Cultured mammalian cells lacking PTEN proliferate faster, resist apoptosis, and migrate aberrantly (10-12). Dictyostelium discoideum cells lacking PTEN have elevated PIP 3 and are severely defective in chemotaxis (13).Regulation of PTEN activity, localization, and function are controlled by a variety of mechanisms. NOTCH1, by acting through transcription factors CBF-1 and MYC or HES-1, respectively, has been reported to either increase or decrease PTEN expression (14-16). Another level of regulation is post-translational modification. Acetylation by p300/CBP-associated factor blocks PTEN activity (17). PTEN catalytic activity is negatively regulated by reactive oxygen species under oxidative stress (18-20) by disulfide linkage of catalytic cysteine 124 with cysteine 71 (18...

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Section: Discussionmentioning

confidence: 99%

“…PTEN A4 was also effective at lowering steady-state levels of phosphorylated AKT1 (data not shown and ref. 35). These observations suggest that activity is dependent on extent of membrane binding and that phosphorylation of the C-terminal cluster has an inhibitory effect on membrane association and activity.…”

mentioning

confidence: 99%

A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN

Rahdar

Inoue²,

Meyer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

245

289

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“…K ATP activation by leptin is dependent on actin depolymerization in both cell types (12)(13)(14)(15). The connection between leptin-driven PI3K activity, actin re-modeling, and K ATP opening appears not to be due simply to increased PtdIns(3,4,5)P 3 but may also require coincident inhibition of PTEN protein and lipid phosphatase activity through increased PTEN phosphorylation (12).…”

mentioning

confidence: 99%

“…Instead, leptin inhibited the lipid and protein phosphatase, PTEN, which resulted in increased PtdIns(3,4,5)P 3 levels in the presence of active PI3K (12). Previously, PI3K-dependent leptin signaling had been shown to open ATP-sensitive (K ATP ) channels in rat hypothalamic neurons (13) and in rat and mouse insulin-secreting cells (12,14,15), resulting in cell hyperpolarization and inhibition of firing. K ATP activation by leptin is dependent on actin depolymerization in both cell types (12)(13)(14)(15).…”

mentioning

confidence: 99%

“…Previously, PI3K-dependent leptin signaling had been shown to open ATP-sensitive (K ATP ) channels in rat hypothalamic neurons (13) and in rat and mouse insulin-secreting cells (12,14,15), resulting in cell hyperpolarization and inhibition of firing. K ATP activation by leptin is dependent on actin depolymerization in both cell types (12)(13)(14)(15). The connection between leptin-driven PI3K activity, actin re-modeling, and K ATP opening appears not to be due simply to increased PtdIns(3,4,5)P 3 but may also require coincident inhibition of PTEN protein and lipid phosphatase activity through increased PTEN phosphorylation (12).…”

mentioning

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Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Ning

Miller

Laidlaw

et al. 2009

Journal of Biological Chemistry

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Leptin activates multiple signaling pathways in cells, including the phosphatidylinositol 3-kinase pathway, indicating a degree of cross-talk with insulin signaling. The exact mechanisms by which leptin alters this signaling pathway and how it relates to functional outputs are unclear at present. A previous study has established that leptin inhibits the activity of the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), an important tumor suppressor and modifier of phosphoinositide signaling. In this study we demonstrate that leptin phosphorylates multiple sites on the C-terminal tail of PTEN in hypothalamic and pancreatic ␤-cells, an action not replicated by insulin. Inhibitors of the protein kinases CK2 and glycogen synthase kinase 3 (GSK3) block leptin-mediated PTEN phosphorylation. PTEN phosphorylation mutants reveal the critical role these sites play in transmission of the leptin signal to F-actin depolymerization. CK2 and GSK3 inhibitors also prevent leptinmediated F-actin depolymerization and consequent ATP-sensitive K ؉ channel opening. GSK3 kinase activity is inhibited by insulin but not leptin in hypothalamic cells. Both hormones increase N-terminal GSK3 serine phosphorylation, but in hypothalamic cells this action of leptin is transient. Leptin, not insulin, increases GSK3 tyrosine phosphorylation in both cell types. These results demonstrate a significant role for PTEN in leptin signal transmission and identify GSK3 as a potential important signaling node contributing to divergent outputs for these hormones.Efficient signaling by leptin and insulin is essential for the maintenance of body energy homeostasis, with disruptions in these processes strongly associated with diabetes and obesity (1, 2) and, at least for insulin, neurodegenerative disorders such as Alzheimer disease (3, 4). In recent years there has been a significant increase in understanding the intracellular signaling processes associated with the actions of insulin on a wide variety of cell types (5). However, our knowledge of leptin signaling is less advanced, with most studies indicating that leptin and insulin share many signaling intermediates in common, often leading to similar cellular outcomes (6, 7). In particular, signaling through the STAT (signal transducers and activators of transcription), mitogen-activated protein kinase, and PI3K 3 pathways have been reported extensively in numerous cell types for both leptin and insulin (5, 8).Nevertheless, leptin and insulin can cause differing and sometimes opposing cellular outputs, even on the same cell type. This is demonstrated in hypothalamic neurons, where electrophysiological or imaging studies show differential outcomes for leptin and insulin action (9 -11). Thus, although superficially leptin may utilize the same signaling pathways as insulin, the exact nature of the leptin-induced signaling intermediates and their interplay with one another and with individual effectors is still relatively unknown. Recently, it was demonstrated that although leptin, lik...

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Leptin and Cognitive Function

Harvey

2013

Metabolic Syndrome and Neurological Disorders

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A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cells

Cited by 102 publications

References 40 publications

A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN

A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN

Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Leptin and Cognitive Function

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